Aging and Alzheimer's Disease (AD) are characterized by the accumulation of aberrant proteins and proteins conjugated to ubiquitin. One function of ubiquitin in normal cells is to serve as a molecular marker for the degradation of abnormal or structurally damaged cellular proteins. Thus, one reasonable explanation for the degradation of abnormal or structurally damaged cellular proteins. Thus, one reasonable explanation for the accumulation of ubiquitinated proteins in aged and AD cells is a defect in the proteolytic system normally responsible for their degradation. We have identified and extensively studied a widely distributed protease named the proteasome, that appears to be the protease that degrades ubiquitinated proteins. We have also identified and studied two specific proteasome regulatory proteins that may control its activity in intact cells. The purpose of this work is to test the hypothesis that aging and/or AD cells have a general defect in the process of intracellular protein degradation and that one or more components of the proteasome-catalyzed ubiquitin-dependent proteolytic pathway accounts for this defect. Therefore, we propose to determine whether rates of protein degradation in aged or AD cells in culture are lower than those in young or normal controls. We will also measure the activity of the proteasome system in cell free extracts from these same cells and quantitate level of the various component proteins. These studies should determine whether altered protein degradation is a characteristic of aged or AD cells and identify a possible molecular basis for such a defect.